A mother lode of protection

Between 60 and 95 percent of adults worldwide are infected with herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2) or both. For the vast majority, these infections are nothing more than a periodic nuisance, causing cold sores or genital lesions. But for newborns, these viruses can have devastating consequences: severe damage to the central nervous system, brain inflammation and potentially death. Even with today's best antiviral drug treatments, such as acyclovir, neonatal herpes is fatal in about 15 percent of cases.

Now research conducted in mice offers new hope that neonatal herpes infections might eventually be avoidable by stimulating an immune response in mothers.

The study, published on April 10 in Science Translational Medicine, was led by David Leib at the Dartmouth Geisel School of Medicine and done in collaboration with Harvard Medical School scientists David Knipe, the Higgins Professor of Microbiology and Molecular Genetics, and Donald Coen, professor of biological chemistry and molecular pharmacology, in the School's Blavatnik Institute.

The new findings build on previous work from Leib's lab, which shows that HSV antibodies produced by adult women or female mice migrate to the nervous system of their unborn babies and provide HSV immunity and uses an experimental vaccine for HSV-1 and HSV-2 that Knipe and his colleagues developed at Harvard Medical School. The vaccine candidate, called HSV-2 dl5-29, has shown promise in preclinical animal models at preventing both types of infections.

In phase 1 human trials, the vaccine has been proven safe and capable of inducing an immune response. But it isn't clear whether the vaccine can effectively prevent infection in newborns, who typically acquire HSV-1 and HSV-2 during or shortly after birth as the result of exposure to active maternal infection.

Researchers have long known that the majority of neonatal herpes infections happen when mothers become infected with HSV-1 or HSV-2 during pregnancy, Knipe said, suggesting that babies born to mothers who already had an infection prior to pregnancy might transfer herpes-fighting antibodies to their own offspring.

To test this idea, the researchers collected samples of maternal blood from women previously infected with HSV-1 and HSV-2, as well as cord blood and blood samples from their babies soon after they were born and 18 months later. Tests showed that the sera from these samples all contained antibodies that effectively neutralized these viruses.

To determine if these antibodies could prevent an infection, the researchers took antibody-containing sera from infected animals and gave them to pregnant mice. When their mouse pups were born, tests showed that they were immune to HSV-1.

With good evidence that infection-fighting antibodies transferred effectively to offspring, the researchers turned to the vaccine--a weakened HSV-2 virus that also stimulates immunity toward HSV-1. Experiments showed that mouse pups from mothers immunized before pregnancy not only had antibodies against both viruses in their sera and nerve tissues, but they were also effectively protected against both types of herpes. In addition, foster experiments that involved switching pups between vaccinated and mock-vaccinated mothers suggest that this immunity could arise from either placental and breast milk transfer of antibodies.

In a final experiment, the researchers challenged mice born to either vaccinated or nonvaccinated mothers with a dose of HSV-1 just under what could cause overt disease. Such low-level doses of the virus have been implicated in neurologic disorders in humans, such as schizophrenia and Alzheimer's disease. While pups from the vaccinated mothers displayed normal behavior in a cage, exploring every part of it, those from the nonvaccinated mothers were more likely to display anxious behavior, sticking to the edges of the enclosure rather than exploring the center.

These findings suggest that maternal immunization can protect not only against acute infection, said Knipe, but also against subacute doses of virus that may have long-lasting behavioral impact.

Together, he adds, these vaccines showcase the promise of immunizing mothers to protect offspring. Although this study focused on herpes, he said, the findings may have implications for other viruses with devastating neonatal effects, such as cytomegalovirus and Zika viruses, both which cause microcephaly and other serious neurological problems.

"There is ample evidence that vaccination protects children against a variety of childhood diseases and those protective effects extend into adulthood," Knipe said. "This new study supports the idea that by vaccinating women before they become pregnant, we may be able to protect against some really important diseases before a baby is even born."

"Neonatal herpes infections can have profound and tragic consequences for child and family alike, and we want to change that," said Leib, professor and chair of Microbiology and Immunology at Dartmouth. "Through this research collaboration across multiple institutions we hope to improve the effectiveness of both vaccine and antibody approaches in preventing or ameliorating this devastating neonatal disease."

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